Aqueous suspension suitable for oral administration

ABSTRACT

The present invention provides liquid oral dosage form of lipid lowering agent suitable for oral administration to human or animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national stage filing under 35 U.S.C. § 371of International Application No. PCT/IB2017/053348, filed on Jun. 7,2017, which claims benefit of priority under 35 U.S.C. § 119(a) toIndian Patent Application No. 201621019719, filed on Jun. 8, 2016. Thecontents of each of these applications are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention is related to liquid oral dosage form of lipidlowering compound preferably statin products suitable for oraladministration.

BACKGROUND OF THE INVENTION

Statins are HMG-CoA reductase inhibitors, a class of drug used to lowerthe cholesterol level by inhibiting HMG-CoA reductase. Currentlyavailable in the market either as tablets, capsules, or solutions forinjection. An individual may have difficulty swallowing the usual soliddosage form, and daily injections are difficult to administer. Forchildren, dose management is difficult if tablet to cut or crush becauseof no accuracy of dose. Based on that a patent application US20120270933claims liquid solution comprising statin and at least one solubilizerwith statement that liquid statin formulation are not available due topoor solubility or insolubility

Still using solubilizer there is an increase in the unknown impurity. Soto avoid this in the present invention solubilizer is avoided.

OBJECT OF INVENTION

The primary objective of present invention is to provide liquid oraldosage form of lipid lowering compound.

Another objective of present invention is to provide oralsuspension/solution having dose flexibility for patients who needspecial doses of the drug and have difficulties in swallowing oraldosage forms.

Still another objective of present invention is to provide oralsuspension/solution with improved taste having high patient compliance.

It is yet another objective of present invention to provide process ofpreparation of oral suspension/solution of statin products suitable fororal administration.

It is yet another objective of present invention to provide oralsuspension/solution of atorvastatin products suitable for oraladministration and process for preparation thereof without use ofstabilizer and buffering agent.

SUMMARY OF THE INVENTION

The present invention provides liquid oral dosage form of lipid loweringagent, statin suitable for oral administration to human or animals.These formulations are useful for administration of the lowest dose ofstatin for treatment of high cholesterol level and any diseases due tohigh cholesterol. This liquid oral dosage form formulation statinsinclude atorvastatin, simvastatin, rosuvastatin etc. a preferred isatorvastatin.

DETAIL DESCRIPTION OF THE INVENTION

The present invention relates to suspension of statin products suitablefor oral administration to humans or animals.

Statins are HMG-CoA reductase inhibitors, used for the treatment of highcholesterol level or any disease due to high cholesterol level in humanand animals. Currently available doses of statins are either as tablets,capsules, or solutions for injection. Present invention is liquid oraldosage form of statin for oral administration without use of solubilizerand/or a stabiliser such as an antioxidant. Formulation of presentinvention is useful even to administer the lowest dose of thecomposition.

This liquid oral dosage form formulation statins include atorvastatin,simvastatin, rosuvastatin etc. wherein preferred is atorvastatin.

Statins are known for poor aqueous solubility and stability but presentinvention provides dosage form without use of stabilizer, bufferingagent and optionally solubilizer.

Common formula of present invention comprises statin between of 0.1 and5% and at least one suspending agent between 0.2 and 6%. In addition thecomposition comprises viscosity modifier, sweetener, flavors, colors,preservatives and water.

In a preferred form of present invention excipients used can be selectedfrom vehicle, co-solvent, preservative, sweetener, chelating agent,buffer, flavoring agent and sweetness/flavor enhancing agent.

Vehicles used in pharmaceutical formulations are mainly liquid baseswhich carries drugs and other excipients in dissolved or dispersedstate. Pharmaceutical vehicles are of two types:

-   -   1) Aqueous vehicles    -   2) Oily vehicles

Aqueous vehicles can be selected from but not limited to purified water,hydro-alcoholic, polyhydric alcohols and buffers, while oily vehiclescan be selected from vegetable oils, oils, organic oily bases oremulsified bases.

Co-solvents are used to increase solubility of drugs that show lowsolubility in water. It is also used to improve viscosity, taste andflavor. Co-solvent system comprises of solvents selected from but notlimited to propylene glycol, glycerin, alcohol, polyhydric alcohol andwater for injection which is used alone or in combination.

Preservatives are included in pharmaceutical solutions to control themicrobial bioburden of the formulation having broad spectrum ofantimicrobial activity, must be chemically and physically stable overthe shelf-life of the product and have low toxicity. Preservative can beselected from group but not limited to alcohol, benzyl alcohol,chlorobutol, chlorocresol, alkyl esters of paraben, phenol, phenylethanol, sodium benzoate, antimicrobial solvents like propylene glycol,chloroform.

Sweetener can be selected from but not limited to sucrose, liquidglucose, glycerol, sorbitol, saccharin sodium, sucrose and aspartame toimpart sweetness to the formulation.

Chelating agent is used for drug stabilization, to maintain potency ofactive ingredients and to stabilize colors and flavors. Chelating agentcan be selected from but not limited to citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid and trisodiumedetate.

pH of the formulation is between 5 and 10 can be controlled and optimizethe physicochemical performance of the formulation by using base orbuffer can be selected from but not limited to sodium acetate, sodiumhydroxide, sodium citrate, sodium phosphate and disodium phosphate.

Flavouring agents are mainly use to increase the palatability andenhance the aesthetic qualities of the formulation. Flavouring agent canbe selected but not limited to oil based flavouring agent such asessential oils including peppermint oil, orange oil, lemon oil etc.

In aspect of present invention, oral pharmaceutical solution ofatorvastatin is formulated which comprises of an active ingredient,atorvastatin and other excipients selected from vehicle, co-solvent,preservative, sweetener, chelating agent, buffer, flavouring agent andsweetness/flavour enhancing agent, wherein pH of formulation ismaintained between 5 and 10, more particularly between 6 and 9.

Oral liquid composition without use of stabilizer, buffering agent andoptionally solubilizer can be oral suspension or oral solution.

EXAMPLES

The present invention can be described by way of example or strategyonly. It is to be recognized that modifications falling within the scopeand spirit of the description or claims, which would be obvious to aperson skilled in the art based upon the disclosure herein, are alsoconsidered to be included within the scope of this disclosure.

Composition is general for oral liquid dosage form of statin is asunder:

Sr. Ingredients for Statin Oral No. Solution Range (% w/w) 1. ActiveIngredient   2-10% 2. Solubilizer 0.0-15% 3. Co-solvent 0.0-15% 4.Suspending agent 0.0-10% 5. Complexing agent  0-5% 6. Sweetner   0-50%7. Flavor 0.0-2%  8. Surfactant  0.0-0.2% 9. Vehicle 0.0-95%

For the composition of atorvastatin 1 mg/ml, drug and excipients withits range are shown below in table:

Strategy I & II With antioxidant and without antioxidant Sr. STRATEGY ISTRATEGY II No. Ingredients 20 mg/5 ml 20 mg/5 ml 1 Atorvastatin 20.0020.00 2 Propylene Glycol 250.00 250.00 3 Carboxymethyl cellulose 33.3333.33 sodium 4 Magnesium Aluminium silicate 66.67 66.67 5Butylatedhydroxyanisole 0.00 2.00 6 Purified water qs 5 ml qs 5 mlManufacturing Process for (Strategy I)

-   -   1. Sodium Carboxymethyl Cellulose were slowly added in 30% W/W        purified water and stir well till clear solution was obtained.    -   2. Dispensed quantity of Magnesium Aluminium silicate was added        in step 1, additional 20% w/w a purified water add in Step 1 and        stir well till all solid mass was get mixed properly i.e.        homogeneously dispersed.    -   3. API was added into propylene glycol and mixed properly where        solubilizer was used. This mixture was added in to step 2 and        stirred through simple stirrer properly to get homogenized        suspension.    -   4. Add 50% w/w of remaining purified water for makeup the        suspension.        Manufacturing Process for (Strategy II)    -   1 Sodium Carboxymethyl Cellulose were slowly added in 30% W/W        purified water and stir well till clear solution was obtained.    -   2 Dispensed quantity Magnesium Aluminium silicate was added in        STEP 1, additional 20% w/w a purified water add in Step 1 and        stir well till all solid mass was get mixed properly at i.e.        homogeneously dispersed RPM (600-800).    -   3 BHA and API was added into propylene glycol and mixed properly        where solubilizer was used. This mixture was added in to step 2        and stirred through simple stirrer properly to get homogenized        suspension.    -   4 Add remaining purified water for makeup the suspension

Result achieved for strategy I and II based on stability are as under:

Trial Stability Strategy I Strategy II condition Initial 25° C./60% RH40 C./75% RH Initial 25° C./60% RH 40° C./75% RH Impurity A 0.05% 0.02%0.02% 0.05% 0.02% 0.05% Impurity C 0.01% ND ND ND ND ND Impurity D 0.02%0.01% 0.01% 0.03% 0.01% 0.01% Lactone 0.03%  0.1% 0.06% 0.04% 0.05%0.05% Ester ND ND ND ND ND ND Unknown 0.08% 0.15% 1.40% 0.12% 0.63%1.10% Impurities (RRT0.74) (RRT0.80) (RRT0.80) (RRT0.74) (RRT0.80)(RRT0.80) Total 0.53% 0.42%  2.1% 0.42% 1.00%  1.7% ImpuritiesConclusion:

On based of 3M 25° C./60% RH, impurity profile of Strategy I & StrategyII, antioxidant having no effective role.

Based on the results achieved with or without use of stabilizer, we havealso tried for avoiding buffering agent as described in strategy III andIV along with avoiding stabilizing agent.

Strategy III & IV With buffering agent without buffering agent STRATEGYSTRATEGY Sr. Ingredients for Atorvastatin Oral III IV No. Suspension 20mg/5 ml 20 mg/5 ml 1. Atorvastatin 20.00 20.00 2. Carboxymethylcellulose sodium 33.33 33.33 3. Magnesium Aluminium silicate 66.66 66.664. Sucralose 50.00 50.0 5. Acesulfame K 5.00 5.0 6. Methylparahydroxybenzoate 5 5 7. Ethyl parahydroxybenzoate 1 1 8. PotassiumDi-Hydrogen Phosphate 0.959 — 9. Di-potassium Hydrogen Phosphate 0.078 —10. Orange flavour 15.0 15.0 Purified water Up to 5 ml Up to 5 mlManufacturing Process for Strategy III

-   -   1. 50% w/w Purified water was heated till the temperature        reached to 80-90° C. Dispensed quantity of Methyl        parahydroxybenzoate and Ethyl parahydroxybenzoate was added in        to this and stirred to get clear solution. Cool down solution at        room temperature.    -   2. Add sucralose, Acesulfame K in step 1, stir well till clear        solution.    -   3. Sodium Carboxymethyl Cellulose were slowly added in step 1,        stir well till clear viscous solution.    -   3 Magnesium Aluminium silicate were add in step 2 stir well till        all solid mass was get mixed properly i.e. homogeneously        dispersed.    -   4 Add and disperse Atorvastatin in 10% w/w purified water in        separate vessel mix properly for 30 min, with high speed        homogenization.    -   5 Step 4 is add in step 3, mix well through simple stirrer till        get homogenized suspension.    -   6 Add Potassium Di-Hydrogen Phosphate, Di-potassium Hydrogen        Phosphate in 20% w/w purified water, add slowly in step 5 to        achieve pH 6.0-9.0    -   7 Add flavour in step 6.    -   8 Add purified water and makeup the volume.        Manufacturing Process for Strategy IV    -   1 50% w/w Purified water was heated till the temperature reached        to 80-90° C. Dispensed quantity of Methyl parahydroxybenzoate        (E218) and Ethyl parahydroxybenzoate (E214) was added in to this        and stirred to get clear solution. Cool down solution at room        temperature.    -   2 Add sucralose, Acesulfame K in step 1, stir well till clear        solution.    -   3 Sodium Carboxymethyl Cellulose were slowly add in step 1, stir        well till clear viscous solution.    -   4 Magnesium Aluminium silicate were add in step 2 stir well till        all solid mass was get mixed properly i.e. homogeneously        dispersed.    -   5 Add and disperse Atorvastatin in 10% w/w purified water in        separate vessel mix properly for 30 min i.e. homogeneously        dispersed.    -   6 Step 4 is add in step 3, mix well through simple stirrer and        get homogenize medium i.e. homogeneously suspension.    -   7 Add flavour in step 6.    -   8 Add purified water and makeup the volume.

The results we achieved for strategy III and IV are as under:

Trial Strategy III Strategy IV 3 M 3 M Stability condition Initial 25°C./40% RH 40 C./25% RH Initial 25° C./40% RH 40 C./25% RH % Impurity AND 0.07 0.07 0.04 0.06 0.06 Impurity C ND ND ND ND ND ND Impurity D 0.030.04 0.05 0.06 0.02 0.02 Lactone 0.05 0.08 0.11 0.18 0.1  0.08 Ester NDND ND ND ND ND Unknown Impurities 0.05 0.25 0.76 0.07 0.09 0.12(0.81RRT) (0.78RRT) (0.78 RRT) (0.80 RRT) (0.79 RRT) (0.79 RRT) TotalImpurities 0.1  0.62 1.4  0.57 0.44 0.44Conclusion:

Based on 3M 25° C./40% RH & 3M 40° C./25% RH impurity profile ofStrategy III & Strategy IV, stabilizer buffering agent is having partialor no effective role.

Strategy V

For effective homogenization. STRATEGY V Sr. No. Ingredients forAtorvastatin Oral Suspension 20 mg/5 ml 1. Atorvastatin 20.00 2.Carboxymethyl cellulose sodium 33.33 3. Magnesium Aluminium silicate66.66 4. Sucralose 50.00 5. Acesulfame K 5.00 6. Methylparahydroxybenzoate 5 7. Ethyl parahydroxybenzoate 1 8. Orange flavour15.0 9. Purified water Up to 5 mlManufacturing Process for Strategy V

-   -   1 50% w/w Purified water was heated till the temperature reached        to 80-90° C. Dispensed quantity of Methyl parahydroxybenzoate        (E218) and Ethyl parahydroxybenzoate (E214) was added in to this        and stirred to get clear solution. Cool down solution at room        temperature.    -   2 Add sucralose, Acesulfame K in step 1, stir well till clear        solution.    -   3 90% quantity of Sodium Carboxymethyl Cellulose were slowly add        in step 1, stir well till clear viscous solution.    -   4 Magnesium Aluminium silicate were add in step 2 stir well till        all solid mass was get mixed properly i.e. homogeneously        dispersed.    -   5 In a separate vessel take 10% v/v of purified water and        remaining qty of sodium carboxymethyl cellulose and disperse        Atorvastatin. Homogenize through high speed for 30 min, achieve        particle size d90 1 micron-15 micron.    -   6 Step 5 is add in step 4, mix well through simple stirrer and        get homogenize medium i.e. homogeneously suspension.    -   7 Add flavour in step 6.    -   8 Add purified water to make up and homogenize through high        speed for 45 min.        Trial Results:

Based on the homogenization trials, final formulation with differentparticle size distribution was evaluated with Reference marketed product(Lipitor 40 mg Film coated tablet) at a dose of 40 mg per volunteer. Andthe results of the bio equivalence (BE) study is as mentioned below:

BE STUDY I: Formulation particle size (D₉₀-22.39 μm) Pharma- cokineticLn-transformed 90% Pa- Geometric Least Squares Mean ConfidenceIntervalrameters TestProduct ReferenceProduct T/R (Parametric) (Units) (T) (R)(%) Lower Upper Cmax 36.1290 53.2937 67.79 52.49 87.56 (ng/mL) AUC0-t164.7519 176.0092 93.60 86.32 101.50 (ng · hr/ mL)

BE STUDY II: Formulation particle size (D₉₀-6.02 μm) Pharma- cokineticLn-transformed 90% Pa- Geometric Least Squares Mean ConfidenceIntervalrameters TestProduct ReferenceProduct T/R (Parametric) (Units) (T) (R)(%) Lower Upper Cmax 55.6268 61.7538 90.08 63.43 127.92 (ng/mL) AUC0-t212.8483 215.5457 98.75 82.91 117.61 (ng · hr/ mL)Conclusion:

Based on above data, (a) stabilizer and buffering agent have partial orno effective role and (b) suitable particle size of API in finishedproduct to get bioequivalent product, can be achieved from effectivehomogenization

Observation from Study 2:

The ratios of geometric least squares means of test product (T) andreference product (R) for Ln-transformed pharmacokinetic parameters(Cmax and AUC0-t) of atorvastatin were found to be 67.79 and 93.60%,respectively for formulation strategy IV (homogenized product with APIparticle size D90=22.39 μm), which is not within acceptable range of90.00-110.00%.

The ratios of geometric least squares means of test product (T) andreference product (R) for Ln-transformed pharmacokinetic parameters(Cmax and AUC0-t) of atorvastatin were found to be 90.08% and 98.75%respectively, which is in between range of 90.00-110.00% for formulationstrategy V (homogenized product with API particle size D90=6.02 μm).Furthermore, the 90% confidence intervals for the ratio of geometricleast squares means for Ln-transformed pharmacokinetic parameter AUC0-tis within the acceptable bioequivalence interval of 80.00-125.00%, whilethat of Cmax is not within the acceptable bioequivalence interval of80.00-125.00% due to limited number of subjects and lower power of thestudy. By adding more number of subjects and higher power in the study,the 90% confidence intervals for the ratio of geometric least squaresmeans for Ln-transformed pharmacokinetic parameter Cmax may be withinthe acceptable bioequivalence interval of 80.00-125.00%.

From the study it was concluded that effective homogenization-particlesize reduction method is required to produce the product havingcomparative pharmacokinetic profile to Innovator product (Lipitor).

The same strategy and manufacturing process can be applicable to allHMG-CoA reductase inhibitors like simvastatin, rosuvastatin.

Further, formulation trials were also tried for atorvastatin oralsolution without using stabilising and buffering agent. Few strategiesare mentioned below:

Atorvastatin oral solution STRATEGY Ingredients for I II III IV Sr.Atorvastatin Oral 20 mg/ 20 mg/ 20 mg/ 20 mg/ No. Solution 5 ml 5 ml 5ml 5 ml 1. Atorvastatin 20.00 20.0 20.0 20.00 2. Propylene glycol 250 —150 — 3. Ethanol — — 5% v/v 20% v/v 4. HPBCD — — — 400 5. Sorbitolsolution 300 300 300 300 6. Peppermint flavor 0.5 0.5 — 0.5 7. Orangeflavor — 0.5 0.5 — 8. Polysorbat 80 1 3 — — 9. Glycerine Up to 5 ml — —Up to 5 ml 10 Purified water — Up to 5 ml Up to 5 ml —Manufacturing Process Strategy I

-   -   1. Add atorvastatin in Propylene glycol mix well till clear        solution obtained.    -   2. Add sorbitol solution in 50% v/v of total quantity of        glycerine mix well to obtain homogeneous mixture.    -   3. Add step 2 in to step 1 mix well.    -   4. Add polysorbate 80 in step 3 to obtain clear viscous        solution.    -   5. Add peppermint in step 4 and mix well till homogeneous        solution obtained.    -   6. Make up the volume with glycerine pH of solution (4.0-7.0)        Manufacturing Process Strategy II    -   1 Add atorvastatin in purified water mix well than add        polysorbate 80 and mix well till clear solution obtain.    -   2 Add sorbitol solution in Step 1 stir well till clear solution.    -   3 Add Orange flavor in step 2 stir well till clear solution.    -   4 Make up the volume with purified water pH of solution        (5.0-9.0)        Manufacturing Process Strategy III    -   1 Add atorvastatin in ethanol mix well in separate vessel.    -   2 Add propylene glycol in step 1 till clear solution obtain.    -   3 Add sorbitol solution in 50% purified water in separate vessel        mix well to obtain homogeneous mixture    -   4 Add Orange flavor in step 3 stir well till clear solution.    -   5 Step 1 add in step 4 stir well till clear solution obtain.    -   6 Make up the volume with purified water. Ph of solution        (5.0-8.0)        Manufacturing Process Strategy IV    -   1 Add atorvastatin in ethanol mix well in separate vessel.    -   2 Add HPBCD in step 1 stir well till complete complex is formed.    -   3 Add sorbitol solution in 50% purified water in separate vessel        mix well to obtain homogeneous mixture.    -   4 Add peppermint flavor in step 3 stir well till clear solution.    -   5 Step 1 add in step 4 stir well till clear solution obtain.    -   7 Make up the volume with glycerine. pH of solution (4.0-7.0)

The same strategy can be applicable to all other HMG-CoA reductaseinhibitors like simvastatin, rosuvastatin, etc.

We claim:
 1. An aqueous suspension for oral administration, consistingof: atorvastatin in an amount of about 0.4% w/w; a suspending agent inan amount of about 2% w/w comprising carboxymethyl cellulose sodium inan amount of about 0.7% w/w and magnesium aluminum silicate in an amountof about 1.3% w/w; a preservative in an amount of from 0.01% w/w to 0.5%w/w; a sweetener in an amount of about 0.1% w/w to 2% w/w; a flavoringagent in an amount of from 0.01 to 2.0% w/w; and a water vehicle;wherein the atorvastatin has a d90 particle size of about 6 μm.
 2. Theaqueous suspension of claim 1, wherein the preservative is selected fromthe group consisting of alcohol, benzyl alcohol, chlorobutol,chlorocresol, an alkyl esters of paraben, phenol, phenyl ethanol, sodiumbenzoate, propylene glycol, chloroform, and a combination thereof. 3.The aqueous suspension of claim 1, wherein the preservative comprises analkyl ester of paraben.
 4. The aqueous suspension of claim 1, whereinthe pH of the aqueous suspension ranges from 6 to
 9. 5. The aqueoussuspension of claim 1, wherein a dose of the aqueous suspensioncomprising 40 mg of atorvastatin has a T/R ratio of from 90% to 110%,wherein T is a Cmax-value of the dose after administration to a human,and wherein R is a Cmax-value of a tablet comprising 40 mg atorvastatinafter administration to the human.